The major determinants of the pharmacologic, addictive and pathologic consequences of alcohol consumption are tissue concentration of ethanol, its hepatic oxidation and duration of exposure. All 3 variables are directly and quantitatively influenced by the actions of the enzyme, alcohol dehydrogenase (ADH). Hence, delineation of the properties of the enzyme is fundamental to our understanding of the biochemical basis of alcoholism and alcohol-induced disease states. Human livers contain multiple molecular forms of ADH, the number of amounts of which vary, dependent upon the genetic background and state of health of donors. The primary objective of this continuing research program is the isolation and characterization of the properties of ADH isoenzymes in human livers and the examination of the biochemical nature of the genetic differences in isoenzyme distribution between individuals and among racial groups. Toward these ends, the more than 12 previously identified and newly discovered isoenzymes will be individually isolated by affinity and ion-exchange chromatographic techniques and their kinetic, physical and chemical properties delineated. Current studies indicate that several of them may differ markedly from the remainder in kinetic properties. Of particular interest will be the low pH-optimum (7.0) for activity enzyme forms recently discovered in Black-Americans and the intermediate pH-optimum (8.5) for activity forms present in Asian-Americans. The structural relatedness of the different isoenzyme forms will be studied by subunit hybridization, peptide mapping, and antibody cross-reactivity. Finally, studies will be initiated in selected individuals to correlate enzyme phenotype with alcohol elimination rates in vivo. These studies should provide a molecular basis of understanding of the genetic variations in alcohol metabolic rate and in susceptibility to the effects of ethanol abuse in humans.